Monday, 23 February 2015

Today’s
post will go against some people’s understanding of autism and inflammatory
bowel disease.

Just
as there is a belief that heavy metals are a problem in autism there is another
is another belief that candida is involved in autism and indeed inflammatory
bowel disease (IBD). Various types of
IBD are highly comorbid with autism, but most people with IBD do not have
autism.

The
most common treatment for candida is an antifungal medicine called
nystatin. This drug is a cheap and
widely available.

But
nystatin has another property, it is a highly effective blocker of the
potassium channel Kv1.3.

Regular
readers will recall that this ion channel is key mediator in the inflammatory
process, it is a target in many inflammatory conditions such as IBD and indeed
autism.Those little helminths (TSO)
parasites that are being researched for both autism and IBD were found to
reduce inflammation by releasing their own Kv1.3 blocker which stops the host
(human or animal) from rejecting them.

Abstract: Background: Autism children were reported to
have gastrointestinal problems that are more frequent and more severe than in
children from the general population. Although many studies demonstrate that GI
symptoms are common in autism, the exact percentage suffering from
gastrointestinal (GI) problems is not well known, but there is a general
consensus that GI problems are common in autism. The observation that antifungal medications improve the
behavior of autism children, encourage us to investigate their intestinal
colonization with yeasts. Aim of the work: The purpose of this work was
to investigate the intestinal colonization with yeasts in autistic patients and
to assess the role of yeast as a risk factor to cause autism behavior. Patients
and methods: The study included 83 cases diagnosed as autistic children
referred from the neuro-pediatric clinic and 25 normal children as a control
group. All children under the study came to Phoniatric clinic, during the
period from 2010 to 2012, complaining of delayed language development with
autistic features. Children in this study were classified into 2 groups;
control and study groups. All children were subjected to interview, E.N.T
examination, language assessment, Childhood Autistic Rating Score (CARS), stool
culture for Candida albicans, complete audiological and psychometric
evaluation. Results: There
was significant relation between the autistic children and heavy growth of
Candida albicans in stool culture. Conclusion: The high rate of Candida
albicans intestinal infection in autistic children may be a part of syndrome
related to immune system disorders in these patients.

Conclusion: Candida albicans infection may be a part
of syndrome related to the immune system and depends on genetic basis of
autism, or Candida albicans may be etiological factor lead to excessive ammonia
in gut which is responsible of autistic behavior in children. More researches are
needed to clarify the exact mechanism by which Candida albicans affects
autistic children.

This
study was done by James Adams (of the Autism Research Institute, former home of
DAN). According to Wikipedia, Adams'
research has been described as "a laundry list of autism woo"; I think he is well intentioned.

You
would have expected him to find Candida, but he did not.

Note
that they did not find any parasites either, although they did give up testing
after the first 20 results were negative (not very scientific, I think). Regular readers will know that some “holistic
doctors” insist that parasites are the cause of autism.

Yeast

The presence of yeast was determined by both
culture and by microscopic observation. Yeast was only rarely observed by
culture in the autism or typical groups, and the difference between the two
groups was not significant, as shown in Table ​Table5.5. Yeast was
more commonly observed microscopically, but again the difference between the
two groups was not significant.

Parasitology

The parasitology test was used on
the first 20 autism samples only, which were all negative. It was then decided
to do no additional testing on other samples

The finding that yeast levels
were similar in both the autistic and control group is interesting, as there
has been a great deal of speculation that yeast infections are a major problem
in autism. Our data
indicates that yeast is present at normal levels in the stool of this group of
children with autism. A study by Horvath and Perman [21]
reported that 43% of children with autism undergoing endoscopies had a positive
fungal culture for yeast in their duodenal juice, vs. 23% of age-matched
controls with other gastrointestinal problems requiring endoscopies. Since
their study involved children with severe enough symptoms to warrant
endoscopies, the greater symptom severity may explain some of the difference
with our study. Since the survey by the Autism Research Institute of
over 25,000 parents' reports that parents find antifungals to be one of the
most effective medications for improving behavior [44], our findings are puzzling. It is
possible that children with autism are more sensitive to even a normal level of
yeast. Also, it is possible that antifungals have other
effects, such as reducing inflammation.

Which Study to believe?

I have to say that I give more credence to the first study, which is from Egypt.

I
think that autism in Egypt is likely to be the “real deal”. People with severe autism will likely have
associated auto-immune/inflammatory conditions and this will include abnormal
GI conditions.

Also, the more severe the autism, the more restrictive the diet is likely to be,
which will affect what grows inside the intestines.

Ion Channels and Channelopathies

Ion
channels are complex, but fortunately there are not that many of them, unlike
genes.

A
good source of information is provided by École polytechnique fédérale de Lausanne, on the banks of lake Geneva. On their Channelpedia site you can see a nice
entry on the potassium channel Kv1.3. It
may all look rather too complicated, but there under the Scorpion toxin, is a very
common drug, Nystatin.

Interactions

PAP-1

MbCD and MbCD/C

Zn

Leukocyte Subunits effect Kv1.3

Cluster at C-terminus

Kv1.3 associates with Kv1.5

Kv1.3 forms heteromeric channels

Scorpion toxin ADWX-1 is a pore blocker of
Kv1.3 channel without affecting its kinetics

Nystatin

The concentrations for nystatin and its structural
analog, amphotericin B, required to produce half maximal inhibition (IC50) of
the current were estimated to be about 3 and 60 microM, respectively. The
effects of nystatin on the amplitude and inactivation of Kv1.3 currents were
not voltage-dependent. In inside-out patches, tetraethylammonium (TEA) produced
a rapid block of Kv1.3 currents upon the onset of a voltage pulse, while the
inhibition by nystatin developed slowly. When co-applied with TEA, nystatin
potentiated the extent of the TEA-dependent block, and the kinetic effect of
nystatin was slowed by TEA. In summary, nystatin, a compound frequently used in
perforated patch recordings to preserve intracellular dialyzable components, specifically
inhibited the potassium channel Kv1.3 at concentrations well below those
required for perforation

KCa3.1 is related to acute immune responses and Kv1.3
is related to chronic immune responses, the combined administration with
Kv1.3 and KCa3.1 inhibitors is likely to enhance their effects in autoimmune
disorders or graft rejection

We
know that Kv1.3 is widely expressed in the brain, but is it expressed in the
intestines of people with inflammatory/auto-immune conditions?

We
do not have far to look and since we know that ulcerative colitis is comorbid
with autism, we can stick with that

Abstract

BACKGROUND AND AIMS:

Potassium
channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation,
proliferation, and cytokine production and may thus constitute targets for
anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory
bowel disease characterized by excessive T-cell infiltration and cytokine
production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are
markers of active UC. We
hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine
production in patients with UC.

METHODS:

Mucosal biopsies
were collected from patients with active UC (n=33) and controls (n=15). Protein
and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and
pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction
(qPCR) and immunofluorescence, and correlated with clinical parameters of
inflammation. In-vitro cytokine production was measured in human CD3(+) T-cells
after pharmacological blockade of KV1.3 and KCa3.1.

CONCLUSIONS:

High levels of
KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with
production of pro-inflammatory IL-17A and TNF-α in active UC. KV1.3 may serve as a marker of
disease activity and pharmacological blockade might constitute a novel
immunosuppressive strategy.

So
now we have some evidence that Kv1.3 is involved in the inflammatory response
within the intestines of people with inflammatory bowel disease (IBD).

Now
we just need to look at what happens when you give Nystatin to people with IBD.

Since
we do have to link all this back to Candida, let us look for people with IBD
claiming that the problem was all about Candida.

If
you google Crohns disease (a type of ulcerative colitis/IBD) you will find
numerous reference to the benefit of Nystatin and again the assumption that
“yeast overgrowth” is somehow the cause of the disease. Lots of "holistic" doctors etc.

Why do so many people with autism
benefit from Nystatin?

We
have seen why some people with GI inflammation should find Nystatin very
helpful, it will act locally as an immuno-suppressant.

By reducing this inflammation there will be a
reduction in inflammatory cytokines like IL-6.
But the whole idea of Nystatin being safe for children with autism is
that it does not enter the blood stream, in stays inside the intestines.

Leaky Gut

Many
people subscribe to the notion of the “leaky gut” in autism. If indeed the gut was leaky, the Nystatin
might leak out. It would then act as a
Kv1.3 blocker elsewhere in the body. It may, or
may not, be able to cross the blood brain barrier.

There
is now some scientific evidence to show that
“leaky gut” is a real phenomenon.

In
people with ulcerative colitis, of course the gut is leaking. Blood is coming in and therefore other
things can flow the other way.

In healthy people, Nystatin will stay almost entirely where it should, within
the intestines. In people with “leaks”
it would seem likely that some will leak out.
In these people we might expect a greater effect.

We
do know that inflammatory activity within the gut can transmitted elsewhere in
the body via the vagus nerve. This means
that reducing inflammation within the GI will reduce the pro-inflammatory
signalling sent around the body via the vagus nerve, even with no "leaky gut".

This
may indeed sound very odd, but very promising results are now being found in
treating people with arthritis (an inflammatory condition, where IL-6 plays a
key role) using implanted electrical devices that affect the vagus nerve. Vagus nerve stimulation is not pseudoscience, even though it does sound like it should be.

My conclusion

The
“father” of ARI and the DAN movement, Dr Bernard Rimland, a research psychologist,
suggested that a small proportion of people diagnosed with autism had nothing
more than an overgrowth of candida, caused by the frequent use of antibiotics.

It does seem that very many things
can lead to “autism” and this diagnosis is now equally applied to people with
very mild symptoms and those with debilitating ones. I imagine that Bernie may indeed have been
right; in a small number of people the problem may indeed be yeast. However, given the relatively large number of
people with autism (and IBD) who find Nystatin very helpful, I think the real issue is inflammation and KV1.3. The people who respond to Nystatin would very
likely also respond to those TSO helminths, and even Stichodactyla
toxin (see later).

One problem with regular use of
antifungal medication is that you are going to kill off not just the
candida. A healthy gut is supposed have
all sorts of things living in it.

For
me, the conclusion is to go back to the ion channels and look not just for KV1.3
blockers but also KCa3.1.
There are plenty of people doing just this, but not for autism, for
example:-

Abstract

Under normal conditions in the brain, microglia play roles in homeostasis
regulation and defense against injury. However, over-activated microglia secrete proinflammatory and
cytotoxic factors that can induce progressive brain disorders, including
Alzheimer's disease, Parkinson's disease and ischemia. Therefore, regulation of
microglial activation contributes to the suppression of neuronal diseases via
neuroinflammatory regulation. In this study, we investigated the effects of
acacetin (5,7-dihydroxy-4'-methoxyflavone), which is derived from Robinia
pseudoacacia, on neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2
cells and in animal models of neuroinflammation and ischemia. Acacetin significantly inhibited
the release of nitric oxide (NO) and prostaglandin E(2) and the expression of
inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV-2 cells. The
compound also reduced proinflammatory cytokines, tumor necrosis factor-α and
interleukin-1β, and inhibited the activation of nuclear factor-κB and
p38 mitogen-activated protein kinase. In an LPS-induced neuroinflammation mouse
model, acacetin significantly suppressed microglial activation. Moreover,
acacetin reduced neuronal cell death in an animal model of ischemia. These results suggest that
acacetin may act as a potential therapeutic agent for brain diseases involving
neuroinflammation.

In humans, a polymorphism in the Kv1.3 promoter is
associated with impaired glucose tolerance and with lower insulin sensitivity (11). These results suggest
that selective Kv1.3 blockers might have use in the management of obesity and
insulin resistance

Because pancreatic beta cells, which
have Kv3.2 channels, are thought to play a role in glucose-dependent
firing, ShK, as a Kv3.2 blocker, might be useful in the treatment of
type-2 diabetes.

You
may recall we already saw in this blog the older people taking Verapamil (for
heart problems) did not develop type 2 diabetes. According to the table below,
ShK toxin is a Kv3.2 blocker in humans, but Verapamil only
works in rats.

Since
it looks like selective Kv1.3 blockers may prevent/treat obesity, you can
expect them to be attractive targets for pharmaceutical companies. This is a disease of the 21st
century.

The
spin-off might later be a cost-effective treatment for inflammatory conditions
like IBD and autism.

The
clever new arthritis treatments, that could be used in autism, are hugely expensive.

14 comments:

Hi Peter,I wanted to ask about Nyastatin for a while. I just found this post on your blog, the reason is my son got diagnosed after we started him on QVAR and flovent (steroid inhalers for asthma) and his stimming went through the roof, the doc told us candida is a side effect and I should wash his mouth, always wondering if the candida increased increaed in his gut.In the post above, it seems like Verpamil would affect behavior in a similar way as Nyastatin - true?ThanksBK

Yes, I am suggesting that Nystatin may be helping some people with autism for reasons unconnected with Candida.

The reason why steroid inhalers are safe is that the steroid does not enter the bloodstream.

The drug producer does say that:-

•Localized infections with Candida albicans have occurred in the mouth and pharynx in some patients receiving QVAR. Advise rinsing of mouth after use. If oropharyngeal candidiasis develops, QVAR may need to be temporarily interrupted under close medical supervision

My 6 year old daughter with severe autism non verbal-has associated auto-immune/inflammatory conditions this include abnormal GI conditions. Nystatin one of best interventions first day she was given spoke a four word sentence not been repeated unfortunately words very few come and go never retained.Been to well recognised gastrologist in Europe, who insists she has no yeast ,but chronic Hpylori low white blood count.gave ketotofin and later treated hpylori miracle drug ketotofin pain in tummy stopped aggresion sib stopped unfortunately reaction to ketotofin xyzal now given not as effective always bad reaction to calcium supplements,reacts to zinc,and probably magnesium and potassium.Nalcrom great,eye drop,loratadine all helping ,More gains NAC,Australian sprouts thanks to Agnieszka and yourself .what do you think would be helpful.I am terming her classic.Little success with natural supplements great success with pharmaceuticals

I would suggest you read about Agnieszka's study on verapamil, the link is at the top of the blog on the right side opposite the date. I think your child very well may be a responder and I am sure if you contact her via the email in her guest post she will answer your questions and hopefully enroll in her case series.

Hi Peter, another paper this fall linked Candida tropicana species with Crohn's disease. https://www.sciencedaily.com/releases/2016/09/160920151435.htm. I am wondering if you have found any papers on if Fluconazole (Diflucan) also affects potassium channels - it is a more systemic anti-candida agent and also it is used in autism treatment by DAN doctors - I would imagine it would have a better effect than Nystatin due to this systemic effect, however have not tied it yet. I also could not find how it affects potassium channels but maybe I am not searching correctly.

Fluconazole is known to lower the level of potassium in your blood, which would likely affect potassium channels.

With many DAN interventions they have found something that affects a minority and then assume it affects everyone. I think some people likely do have odd behavioural reactions to a candida infection, like after using some steroid oral inhalers. This does not mean everyone has a problem and then some people's lives get taken over by thinking candida is driving their type of autism.

Valtrex, which is used by DAN type doctors, is meant to treat the herpes virus. Apparently in some people it increased the level of glutathione, which means it has antioxidant properties. Viral infections would not be positive for anyone's health, but treating a non-existing virus may be unwise. As usual you have to draw the line yourself between fact and fiction. Some people with autism will have picked up a herpes virus and Valtrex should indeed help them.

Not so fast Peter! Acyclovir is known to inhibit IDO, and it is easy to imagine valacyclovir/valtrex having the same effect.

And as IDO is so very closely involved in (messing up) tryptophan metabolism - read dysregulate serotonin/melatonin/niacin/quinolinic acid levels ... it is likely that tweaking IDO activity and lowering its levels would have positive effects in some.

My son responds within hours to Diflucan. I can't believe if it was truly yeast, that he would respond so quickly. The main major improvement is sleep. Solid 11-12 hours of sleep. Normally, he wakes in the middle of the night and goes to someone else's bed. Sometimes can be up for several hours. He is positive for N Type calcium channel binding antibody and Neuronal AChR, Ganglionic (Alpha-3). I have read and read about the calcium antibodies, but I can't make much sense of it and how it may be related to my son's autism. He is taking Bumetanide now. Interestingly, he has had positive serum for the calcium antibody for over a year, he has been taking Bumetanide for 1 month and this last panel came back with calcium antibody WNL. Still positive for the AChR. Any thoughts on what the calcium antibodies may have to do with autism and what the Diflucan may really be doing? Is there an off label effect happening? Thanks,

I found this article from 2017 that describes how the Kv1.3 channel (relevant for chronic auto-immunity issues and blocked by Verapamil) and the KCa3.1 channel (relevant in acute immunity reactions) work together in T-cells. It reveals that the KCa3.1 channel can compensate for the other channel and also that it is the number of exposures to antigen that dictates whether Kv1.3 or KCa3.1 is the prevalent channel.

"we demonstrate that Kv1.3 is the predominant functionally active channel in T cells subjected to repeated specific antigen exposure and that KCa3.1 compensates for loss of functional Kv1.3 as in the presence of Kv1.3 inhibitors.""The mechanisms responsible for conversion from KCa3.1 to Kv1.3 dependency remain to be elucidated"

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By Agnieszka Wroczyńska, MD, PhD, Medical University of Gdansk, Poland In June 2014 my son with severe autism ...

About this Blog

This blog is mainly a review of the science behind autism, looking for pointers to effective treatments for classic autism.The first treatment, Bumetanide, I stumbled upon before starting this blog.The last treatment, tiny doses of Clonazepam, came from a recent paper, highlighted by a regular follower of this blog.You do need some basic scientific knowledge, but putting our minds together, we can make our own medical advances; so all comments and case histories are very welcome.

If your interest is regressive autism, very likely the cause is mitochondrial disease. Classic autism therapies may well be ineffective. Mitochondrial disease can be diagnosed and treated.

Quack-free zone - Science only

About Me

I am an independent researcher, trawling through the scientific literature and doing some experiments along the way. I am not a doctor. I do have a Master's degree from a top science-only university and another one from a top business school. More relevant is my motivation.

I am developing a novel drug therapy, the Autism Polypill, to treat classic early-onset autism, since this is the type that affects my son. His type of autism is characterized by autistic behaviours, pollen allergy, asthma, some SIB, high serotonin, high cholesterol, high euthyroid, high IGF-1, but without seizures, GI problems, food intolerance or severe MR. I think that ADHD and Asperger's are likely to be very mild forms of this phenotype of autism. Many other types of "autism" are entirely different. As this blog shows, at least classic autism is treatable using today's drugs.